4.1 Cardiovascular Disease
Background: In prior work, we have evaluated the biomarker research portfolio for cholesteryl ester transfer protein (CETP) inhibitors as a treatment for cardiovascular disease (see appendix A). We considered that CETP inhibitors effectively modulate their target biomarker (raising the patient’s HDL cholesterol), but to date, none of them have produced any corresponding improvements in the clinical outcome of reducing the incidence of cardiovascular disease. The concept of using triglycerides as a surrogate marker predictive of cardiovascular disease has likewise been at the center of some of the most important regulatory developments of the last year. The maker of a fish oil preparation that lowered triglycerides in patients with extremely high levels brought legal action against FDA when the agency refused to approve promotion of this product among patients with moderate levels to prevent cardiovascular disease (an association that has not been demonstrated). This litigation, essentially over the clinical implications of the triglyceride biomarker, has now called the agency’s entire regulatory legitimacy into question.
Aim: To examine biomarkers that modulate HDL, LDL, and triglycerides and their interactions with all drug classes intended to affect them. We hypothesize that the predictive utility of lipid-modifying biomarkers will be limited to specific drug classes.
Approach: We will conduct a systematic literature search on approved or investigational drugs that use lipid-modulating mechanisms as a treatment for cardiovascular disease. The results of this search will populate our “master list” of drugs and drug candidates, and we will conduct a keyword search of Medline, Embase, and Clinicaltrials.gov using these drug names to capture all published clinical trial reports and trial registration records. The published trial reports will be linked to their original registration record and then extracted for study demographics, clinical details, design properties, and outcome data. We will then perform a descriptive analysis of research and reporting activities, statistical meta-analysis of outcomes and data trends, and AERO graphing to chart the utility and predictive value of these biomarkers as a function of the individual therapeutic agents and the drug class.
A pilot search for this protocol identified 58 lipid-modifying agents and 1,197 registered trials of these agents in Clinicaltrials.gov.